prostaglandin-d2 and Hyperemia

The effects of topically applied prostaglandin (PG) D2 and BW245C, a potent PGD2 agonist, on intraocular pressure (IOP) were studied in normotensive human volunteers. Doses of 5 and 10 micrograms PGD2 induced a mean reduction in IOP of 0.8 and 1 mmHg, respectively. At a dose of 50 micrograms, hypotension was preceded by initial hypertension (4 mmHg at 0.5 h) and the magnitude of the mean IOP reduction during the hypotensive phase was 1.1 mmHg. The application of BW245C (2.5 micrograms) induced an IOP change similar to that observed following treatment with 50 micrograms PGD2. Side effects caused by these compounds included conjunctival hyperemia, itching, and foreign-body and mild burning sensations. However, miosis and signs of intraocular inflammation were not observed. These results indicate that although PGD2 and BW245C are effective in reducing human IOP, their clinical usefulness as anti-glaucoma drugs may be limited by the extraocular side effects.

Topics: Administration, Topical; Adult; Conjunctiva; Double-Blind Method; Female; Humans; Hydantoins; Hyperemia; Intraocular Pressure; Male; Prostaglandin D2; Pruritus; Tonometry, Ocular

The aim of our study was to investigate the adaptation of the hypothalamic circulation to chronic nitric oxide (NO) deficiency in rats. Hypothalamic blood flow (HBF) remained unaltered during chronic oral administration of the NO synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME, 1 mg/ml drinking water) although acute NOS blockade by intravenous l-NAME injection (50 mg/kg) induced a dramatic HBF decrease. In chronically NOS blocked animals, however, acute l-NAME administration failed to influence the HBF. Reversal of chronic NOS blockade by intravenous l-arginine infusion evoked significant hypothalamic hyperemia suggesting the appearance of a compensatory vasodilator mechanism in the absence of NO. In order to clarify the potential involvement of vasodilator prostanoids in this adaptation, cyclooxygenase (COX) mRNA and protein levels were determined in the hypothalamus, but none of the known isoenzymes (COX-1, COX-2, COX-3) showed upregulation after chronic NOS blockade. Furthermore, levels of vasodilator prostanoid (PGI(2), PGE(2) and PGD(2)) metabolites were also not elevated. Interestingly, however, hypothalamic levels of vasoconstrictor prostanoids (TXA(2) and PGF(2alpha)) decreased after chronic NOS blockade. COX inhibition by indomethacin but not by diclofenac decreased the HBF in control animals. However, neither indomethacin nor diclofenac induced an altered HBF-response after chronic l-NAME treatment. Although urinary excretion of PGI(2) and PGE(2) metabolites markedly increased during chronic NOS blockade, indicating COX activation in the systemic circulation, we conclude that the adaptation of the hypothalamic circulation to the reduction of NO synthesis is independent of vasodilator prostanoids. Reduced release of vasoconstrictor prostanoids, however, may contribute to the normalization of HBF after chronic loss of NO.

Topics: Adaptation, Physiological; Animals; Arginine; Cerebral Arteries; Cerebrovascular Circulation; Circle of Willis; Cyclooxygenase Inhibitors; Dinoprostone; Enzyme Inhibitors; Epoprostenol; Hyperemia; Hypothalamus; Male; Nitric Oxide; Nitric Oxide Synthase; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Prostaglandins; Rats; Rats, Wistar; Vasodilation; Vasodilator Agents

Studies were carried out of the effects of topically applied prostaglandin (PG) D2 and its metabolites and analogues on the intraocular pressure (IOP) in rabbits, and the results were compared with those of studies using PGE2 and F2 alpha. The application of PGD2 (0.4-250 micrograms) reduced the IOP, in a dose-dependent manner without causing a hypertensive phase. The hypotensive effect was observed within 30 minutes after the application and lasted for over 7 hours. Higher doses of PGE2 (10, 50 micrograms) or PGF2 alpha (50 micrograms) caused initial IOP elevation followed by a prolonged hypotensive phase. Lower doses of PGF2 alpha (2, 10 micrograms) caused a prolonged (over 7 hours) reduction in the IOP following a latency of over 2 hours. The IOP reduction by 2 micrograms of PGE2 lasted for 5 hours. No miotic response followed the use of these PG's. Conjunctival and iridal hyperemia, aqueous flare, irritation (defined by lid-closing), and aqueous protein content were examined at equi-hypotensive doses of the three PG's (50 micrograms for PGD2, 2 micrograms for PGE2, and 10 micrograms for PGF2 alpha). PGE2 was the strongest in causing these side effects, followed by PGF2 alpha. PGD2 did not cause any of these responses except for some development of conjunctival hyperemia. All of the 4 PGD2 metabolites were ineffective in reducing IOP. Among 6 PGD2 analogues, BW245C, PGD3, and PGD2 methyl ester more effectively reduced IOP than did PGD2. PGD1 and 16,16-dimethyl PGD2 were not effective.

Topics: Administration, Topical; Animals; Aqueous Humor; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Hyperemia; Intraocular Pressure; Iris; Prostaglandin D2; Rabbits; Reflex, Pupillary; Time Factors; Tonometry, Ocular